The basal ganglia connects the cerebral cortex to brain systems that generate behavior. The striatum receives sensory input from the glutamatergic neurons of the neocortex. More than 95% of the neurons of the striatum are the GABAergic medium spiny neurons which are involved in a number of psychomotor functions. The activity of these neurons is modulated by dopamine. Dopamine exerts its functions on cellular activity through G-protein coupled receptors (e.g., D1, D2, D3, D4, and D5 receptors) and aberrant dopamine signaling has been implicated in a number of diseases such as schizophrenia, psychoses, Parkinson's disease, movement disorders, and other neuronal disorders such as attention deficit hyperactivity disorder, depression, and addiction.
Parkinson's disease is characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta. Treatments for Parkinson's disease have focused on the replacement therapies to counteract this loss of dopamine input to the striatum either by L-dopa which is a dopamine precursor or by the administration of dopamine agonists such as pramipexole or ropinirole. Although these treatments are effective, the need for improved medications exists. The direct dopamine agonists are less effective than L-dopa, which despite being the most effective medication has a short half-life, and the resulting fluctuation in plasma concentrations is associated with the onset of dyskinesias. Dopamine agonists with improved efficacy and longer half-lives that produce a more constant plasma exposure are predicted to be improved medications for Parkinson's disease.
In contrast, schizophrenia is associated with an increase in striatal dopamine tone, particularly in the indirect pathway. Accordingly, the clinical efficacy of current antipsychotics correlates with their efficacy as D2 antagonists. However, these agents are known to produce extrapyramidal and other motoric adverse effects (Parkinsonism, dystonia, akathisia, tardive dyskinesia) following acute and chronic dosing. One pharmacological feature of many anti-psychotic drugs is that they typically block the D2/β-arrestin/Akt-GSK pathway which has long been implicated in schizophrenia while having different effects at the c-AMP pathway.
Dopamine partial agonists have been described as the “third generation” antipsychotics. These differentiate from the first and second generations in that their pharmacological effects are dependent on dopamine tone and the expression levels and receptor reserve. For instance, aripiprazole has been reported to be a partial agonist at the presynaptic D2 autoreceptors and in conditions of low dopamine tone. In fact, partial agonists will have a greater efficacy at these receptors due to their high receptor reserve. However, under conditions of high dopamine, as in schizophrenia, low efficacy partial agonists, such as aripiprazole, are effective antipsychotics with reduced motoric side effects due to an incomplete blockade of dopamine signaling in the striatum.
CNS disorders affect a wide range of the population with differing severity. For example, schizophrenia is a psychopathological disorder of unknown origin, which usually appears for the first time in early adulthood and is marked by characteristics, such as, psychotic symptoms, phasic progression and development, and deterioration in social behavior and professional capability. Characteristic psychotic symptoms include disorders of thought content (e.g., multiple, fragmentary, incoherent, implausible or simply delusional contents, or ideas of persecution) and of mentality (e.g., loss of association, flight of imagination, incoherence, or incomprehensibility), as well as disorders of perceptibility (e.g., hallucinations), emotions (e.g., superficial or inadequate emotions), self-perceptions, intentions, impulses, and inter-human relationships, and psychomotoric disorders (e.g., catatonia). Other symptoms are also associated with this disorder. See, e.g., Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., American Psychiatric Association (1997) (DSM-IVT™).
Schizophrenia can be classified into various subgroups. For example, the paranoid type is characterized by delusions and hallucinations and absence of thought disorder, disorganized behavior, and affective flattening. The disorganized type, also named hebephrenic schizophrenia, is characterized by the presence of both thought disorder and affective flattening. The catatonic type is characterized by prominent psychomotor disturbances, including symptoms of catatonic stupor and waxy flexibility. In the undifferentiated type, psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types have not been met.
The symptoms of schizophrenia normally manifest themselves in three broad categories, i.e., positive, negative and cognitive symptoms. Positive symptoms are those that represent an excess of normal experiences, such as hallucinations, disorganized speech, and delusions. Negative symptoms are those where the patient suffers from a lack of normal experiences, such as anhedonia, lack of motivation, inability to experience pleasure, and lack of social interaction. The cognitive symptoms relate to cognitive impairment in schizophrenics, such as lack of sustained attention, impairment of memory, and deficits in decision making. The current anti-psychotics are somewhat effective in treating the positive symptoms but are less effective in treating the negative or cognitive symptoms. For instance, the current typical or atypical anti-psychotics do not address cognitive or negative symptoms of schizophrenia, and only treat the positive symptoms in approximately 40% of patients.
Cognitive impairments include a decline in cognitive functions or cognitive domains, e.g., working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving, e.g., executive function, speed of processing and/or social cognition. In particular, cognitive impairment may indicate deficits in attention, disorganized thinking, slow thinking, difficulty in understanding, poor concentration, impairment of problem solving, poor memory, difficulties in expressing thoughts, difficulties in integrating thoughts, feelings and behavior, or difficulties in extinction of irrelevant thoughts.
These and other CNS or neurological disorders, such as, Parkinson's disease, movement disorders, affective disorders, addiction, among others, continue to affect the health and quality of life of many patients. Thus, there remains a great need for effective treatments of various CNS or neurological disorders, with reduced undesirable side effects.
Citation of any references in this Section of the application is not to be construed as an admission that such reference is prior art to the present application.